Pressurized metered dose inhalers (MDIs) are widely used devices for the delivery of medicaments to the respiratory tract by inhalation via the oral and nasal routes. Though MDIs are used primarily for topical delivery of drugs to the respiratory tract for treatment of such diseases as asthma and chronic obstructive pulmonary disease (COPD), there is increasing interest in their use for systemic drug delivery. Classes of medicaments commonly delivered by MDIs include bronchodilators (e.g., beta-agonists and anticholinergics), corticosteroids, and anti-allergics. See Anthony Hickey, Pharmaceutical Inhalation Aerosol Technology, Marcel Decker, New York (2004) for a general background on this form of therapy.
MDI formulations are comprised of, at least, a medicament and a propellant. MDI formulations may further comprise one or more excipients other than propellant.
MDI formulations are generally characterized as either solutions or suspensions. A solution formulation comprises the medicament dissolved or solubilized in propellant or in a mixture of propellant and one or more excipients. A suspension formulation contains the medicament in the form of particles which are dispersed in the propellant or in a mixture of propellant and one or more other excipients.
Traditionally, the propellant system used in MDIs has consisted of one or more chlorofluorocarbons (CFCs), such as Freon 11 (CCl3F), Freon 12 (CCl2F2), and Freon 114 (CF2ClCF2Cl). However, the CFC propellants are now believed to provoke the degradation of stratospheric ozone and thus their production and use are being phased out.
Hydrofluoroalkane (HFA) propellants, particularly 1,1,1,2-tetrafluoroethane (HFA-134a) and 1,1,1,2,3,3,3,-heptafluoropropane (HFA-227), are currently favored as non-ozone depleting alternatives to the CFC propellants for respiratory drug delivery. Other alternatives to CFCs have been proposed, including dimethyl ether and low molecular weight hydrocarbons, such as propane and butane.
The efficiency of an aerosol device, such as an MDI, is a function of the dose deposited at the appropriate site in the respiratory tract. Deposition is affected by several factors, of which one of the most important is the aerodynamic particle size. The distribution of aerodynamic particle sizes of solid particles and/or droplets in an aerosol can be characterized by their mass median aerodynamic diameter (MMAD, the diameter around which the mass aerodynamic diameters are distributed equally) and geometric standard deviation (GSD, the measure of variability of the aerodynamic particle diameters). Aerosol particles of equivalent MMAD and GSD have similar deposition in the respiratory tract irrespective of their composition.
For inhalation therapy, there is a preference for aerosols in which particles for inhalation have an MMAD of about 0.5 to 100 μm, depending on the intended site of deposition. Particles smaller than 0.5 μm may be exhaled, and particles larger than 100 μm may clog the metering valve or actuator orifice.
For inhalation therapy targeting the lungs, there is a preference for aerosols in which the particles for inhalation have an MMAD of about 0.5 to 10 μm, more preferably about 0.5 to 5 μm, and most preferably about 0.5 to 3 μm. Particles larger than about 5 μm in diameter are primarily deposited by inertial impaction in the oropharynx, particles of about 0.5 to 5 μm in diameter are ideal for deposition in the conducting airways, and particles of about 0.5 to 3 μm in diameter are desirable for aerosol delivery to the lung periphery.
For inhalation therapy targeting the nose, where the medicament is either for the topical treatment of tissues within the nose, or to be absorbed, so as to have a systemic effect, via the nasal mucosa (i.e., via the so called intranasal route), there is a preference for aerosols in which the particles for inhalation have an MMAD of about 5 to 100 μm, preferably about 5 to 50 μm, more preferably about 5 to 25 μm, or, when penetration beyond the nasal cavity is undesirable, within the range of about 10 to 100 μm, preferably about 10 to 50 μm and more preferably about 10 to 25 μm.
Numerous methods are known in the art for the preparation of suspension aerosol formulations for MDIs. The known methods generally comprise the mixing of pre-formed medicament powders, which are of a size suitable for inhalation therapy, with propellant and optionally one or more other excipients. Control of the particle size distribution of the aerosol particles generated from the suspension aerosol formulation is accomplished primarily via control of the particle size distribution of the medicament powders used to prepare the formulation. Thus, considerable care is normally taken to avoid dissolution of the medicament powder in the excipients, as any dissolution of the medicament powder during manufacture of the formulation would result in loss of particle size control.
Conventional methods for generating medicament powders suitable for preparation of formulations for inhalation therapy, such as suspension aerosol formulations for MDIs, include milling (micronization), spray drying, and supercritical fluid recrystallization.
The conventional processes of MDI manufacture are generally characterized as either “pressure filling” or “cold filling”. In pressure filling, the powdered medicament, optionally combined with one or more excipients, is placed in a suitable aerosol container capable of withstanding the vapor pressure of the propellant and fitted with a metering valve. The propellant is then forced as a liquid through the valve into the container. In an alternate process of pressure filling, the particulate drug is combined in a process vessel with propellant and optionally one or more excipients, and the resulting drug suspension is transferred through the metering valve fitted to a suitable MDI container. In cold filling, the powdered medicament, propellant which is chilled below its boiling point, and optionally one or more excipients are added to the MDI container, and a metering valve is fitted to the container. For both pressure filling and cold filling processes, additional steps, such as mixing, sonication, and homogenization, are often advantageously included. See Lachman et al. in The Theory and Practice of Industrial Pharmacy, Lea & Febiger, Philadelphia (1986) for an overview of conventional manufacturing procedures for MDIs.
Salmeterol xinafoate is a selective and potent beta adrenoreceptor stimulant bronchodilator which has been very successfully used by inhalation for the immediate relief of spasm in asthma. Salmeterol is described in British Patent Specification No 2140800. The xinafoate salt of salmeterol is a particularly preferred pharmaceutically acceptable salt for use in inhalation therapy.
Fenoterol is an adrenergic bronchodilator used for the treatment of asthma and COPD. The hydrobromide salt of fenoterol is a particularly preferred pharmaceutically acceptable salt for use in inhalation therapy.
Ipratropium is an anticholinergic bronchodilator used by inhalation for the treatment of asthma, COPD, and allergic rhinitis. The bromide salt of ipratropium is a particularly preferred pharmaceutically acceptable salt for use in inhalation therapy.